Structural basis of neuropeptide Y signaling through Y1 receptor

By Chaehee Park, Jinuk Kim, Seung-Bum Ko, Y. Choi, Hyeongseop Jeong, Hyeonuk Woo, Hyunook Kang, I. Bang, Sang Ah Kim, Tae-Young Yoon and 3 more. 2022

57 citations recorded by the source corpus.

Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (Y1R) in complex with Gi1 protein. The NPY C-terminal segment forming the extended conformation binds deep into the Y1R transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with Y1R extracellular loops, contributing to the high affinity of NPY for Y1R. The structural analysis of NPY-bound Y1R and mutagenesis studies provide molecular insights into the activation mechanism of Y1R upon NPY binding. The human neuropeptide Y (NPY) acts through G-protein coupled receptors and is involved in food intake, stress response, anxiety, and memory retention. Here, the authors show that, unlike in other neuropeptides, both the N-terminal and the C-terminal regions of NPY interact with the NPY receptor 1.

Subfields: Cellular and Molecular Neuroscience, Endocrine and Autonomic Systems, Molecular Biology